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GENOMICS The Next Big Thing in Mining the GenomeA Simpler Tool for Finding Disease Genes and Spotting Genetic Variation Scientists have found a shortcut to help them begin searching for the genetic predispositions for the most widespread medical problems.
David Altshuler's research group bridges the Charles River, based at the Whitehead Institute in Cambridge and Massachusetts General Hospital in Boston. Stacey Gabriel led the recent study to find genetic variations linked to common diseases. (Photo by Graham Ramsay) The genome is a big place, and small changes in single DNA bases can have large consequences. Sorting out the DNA variations that may endow one family with a tendency toward heart disease and another with a risk of arthritis has been compared to looking at a picture of the universe and trying to find a young couple picnicking on a blanket in a park in Chicago. About 99.9 percent of the 3.1 billion base pairs in the human genome are the same from person to person. The remaining 0.1 percent of differences comprises more than 10 million common single-letter genetic variations (and many more rare variants) scattered through the genome. By the numbers, a comprehensive search for the multiple genetic contributions to prevalent conditions such as diabetes and Alzheimer's has loomed as a long, slow, and expensive prospect. Now, potentially simplifying the search, scientists say long blocks of DNA have traveled from one generation to the next with little genetic shuffling. Along any given stretch of chromosome, the genetic variation within these blocks comes in only four or five patterns in different people, according to a new study published online in Science Express May 23 and scheduled for the print version of Science June 21. Even better, researchers think they can test for genetic predispositions for disease block by block, rather than letter by letter. New Basis of InheritanceCalled haplotype blocks, these genome segments often contain one or more genes that make important proteins, many gene regulatory segments, and many fragments with no known function. The haplotype blocks, which apparently have been passed along with few changes through the 10,000-year history of the human species, may turn out to be a basic inherited structural unit of DNA."This is not just a shortcut to finding disease genes, but rather a description of the fundamental nature of how the genome varies in humans," said senior author David Altshuler, a member of the Molecular Biology Department and the Diabetes Unit at Massachusetts General Hospital and HMS assistant professor of genetics and medicine. "It's not the answer to every disease, but it's the framework on which inherited susceptibility to disease has been built," said Altshuler, also director of the medical and population genetics program at the Whitehead Institute Center for Genome Research at MIT.
A new study of genetic variation shows that European, African, and Asian populations share about half of the five common patterns found along any given stretch of DNA. Even before it was published, early results from this study helped launch an international project to map the key markers of common variations in the genome. The project involves many of the same people who are completing the Human Genome Project ahead of deadline, under budget, and on the Internet. The first grants for the "hap map" project will be awarded this summer. The deadline for completion is two years. "It's the next big thing," said Francis Collins, director of the National Human Genome Research Institute, which is leading the effort at the National Institutes of Health. The blocklike structure of human haplotypes was first identified by co-author Mark Daly, a statistical geneticist at the Whitehead, in the course of discovering a gene on chromosome 5 that predisposed people to Crohn's disease. Before the findings were published, Altshuler and Daly teamed up to find out if the observation extended to the rest of the genome and other populations. Last year, they compared notes on preliminary data with colleagues at the Sanger Institute in England, Johns Hopkins University, the University of Washington, and Perlegen Sciences. It became clear that these patterns were general. The low diversity among distinct haplotype blocks opened up what may be an express lane to screening the whole genome. All in the FamilyIn the latest study, first author Stacey Gabriel, scientific director of the Whitehead haplotype program and a member of Altshuler's group, and her colleagues sampled more than 50 randomly chosen regions of the genome involving every chromosome from 275 individuals representing populations from Africa, Europe, and Asia. The researchers drew three major conclusions. First, the human genome can be objectively parsed into simple haplotype blocks each averaging 11,000 to 22,000 DNA letters but only four or five different variations in the letters. Second, the blocks are similar across individuals from Africa, Europe, and Asia, suggesting that a map of haplotypes will have broad utility for most people. Third, the haplotype blocks appear to capture about 90 percent of genetic variation in a region of the human genome."This study is a significant step toward developing a more powerful statistical approach to studying complex human disease," said Daly. "Genetics has not made tremendous inroads in complex disease, even though great effort has been put in during the last 10 to 15 years. As a community, we've come to understand that complex diseases are not caused by single high-penetrance genes, but from more modest risk factors common in populations." The study took advantage of high-throughput genotyping methods based on mass spectroscopy and a map of common single-letter genetic variants published in Nature last year as a companion to the rough draft of the human genome sequence. Altshuler was the senior author on that paper. What Lies BeneathThe support for haplotype mapping as a shortcut to finding the genetic underpinnings of common diseases rests on the increasing popularity of the "common variant-common disease hypothesis," which proposes that most of the genetic contributions to disease susceptibility arise from variants that are relatively common in the susceptible population. According to this hypothesis, which is also based on the history of the human species, a systematic case-control analysis of all common variants in the human genome would reveal the major causative genetic contributions to a disease with considerably greater statistical power than provided by the linkage approach.Not everyone is convinced by the common variant hypothesis, according to a news article in the May 24 Science. Naysayers suggest rare variants are more likely to be the genetic contributors to common diseases. Yet two years ago, Altshuler and Children's Hospital researcher Joel Hirschhorn, HMS assistant professor of genetics, found strong evidence that a common single-letter variation in the gene PPAR-gamma plays a role in the risk of type 2 diabetes in the general population. Carried by 85 percent of the general population, the variant increases the risk of disease by 30 percent. These results have now been confirmed by other researchers and in multiple populations. A growing list of examples supports the hypothesis, including ApoE4 in Alzheimer's disease, Factor V Leiden in deep vein thrombosis, and CCR5 in protection against HIV. "There are different models of population evolution and genetic recombination," Daly said. "This study provides a great deal of hard data scientists can use to go back and refine and improve models of population biology and molecular evolution. For once, genetics worked out to be easier than it could have been. But now we have to do the disease studies, which will not be simple." --Carol Cruzan Morton |
